Pyrimidine derivative, preparation method and use thereof

ABSTRACT

A pyrimidine derivative and the preparation method and use thereof. The said pyrimidine derivative is a diaryl pyrimidine derivative or a diaryl benzo pyrimidine derivative which has the structure shown as the Formula I and IV. 
     
       
         
         
             
             
         
       
     
     Present pyrimidine derivative can be used for the prevention or the treatment of HIV.

FIELD OF THE INVENTION

The present invention belongs to the technical field of medicament, andspecifically relates to a pyrimidine derivative, its phamaceuticallyaccepted salts, its hydrates and solvates, its polycrystalline andeutectics, its precursors and derivatives of the same biologicalfunction, and the preparation method and use thereof.

BACKGROUND ARTS

AIDS, i.e. acquired immune deficiency syndrome, is an epidemic caused byhuman immunodeficiency virus (HIV). During the process of HIV's reversetranscription from mRNA to DNA, reverse transcriptase (RT) performs adecisive function, and therefore becomes an important target for thedesign of anti-AIDS medicines.

Among the current studies of anti-HIV medicines, non-nucleoside reversetranscriptase inhibitors (NNRTIs) have become one of the hotspots in thefield of pharmaceutical chemistry for the benefits of high efficiencyand low toxicity and etc thereof. At present, 4 kinds of reversetranscriptase inhibitors have received FDA approval: Nevirapine,Delavirdine, Efavirenz and etravirine (TMC125). In addition,α-APA089439, HBY097 and TMC-278 are undergoing clinical studies.Classical NNRTIs are only effective against HIV-1, but ineffectiveagainst HIV-2.

Therefore, this field urgently needs a novel medicine to prevent ortreat AIDS.

SUMMARY OF THE INVENTION

The present invention aims at providing a pyrimidine derivative, and thepreparation method and use thereof.

One aspect of the present invention provides a diaryl pyrimidinederivative or pharmaceutically acceptable salts thereof; the diarylpyrimidine derivative has the structure shown as the formula I:

wherein: -a¹=a²-a³=a⁴- represents the structure of a divalent freeradical: —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —N═N—CH═CH—,—N═CH—N═CH—, —N═CH—CH═N—;

-b¹=b²-b³=b⁴- represents the structure of a divalent free radical:—CH═CH—CH═CH—, —N═CH—CH═CH—, —N═N—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—;

R¹ and R² respectively are separately selected from hydrogen, hydroxyl,halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl, substitutedC₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl, amino-group, —NH(OH)—,—N(R⁶)p—;

R¹³ and R¹⁴ respectively are separately selected from hydrogen,hydroxyl, halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl,substituted C₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl,amino-group, —NH(OH)—, —N(R⁶)p—;

R³ and R⁴ respectively are separately selected from hydrogen, hydroxyl,halogen, optionally C₁₋₄ alkyl substituted by cyano-group or —C(═O)R⁶,C₃₋₇ cycloalkyl, optionally C₂₋₆ alkenyl substituted by one or morehalogen atoms or cyano-groups, optionally C₂₋₆ alkynyl substituted byone or more halogen atoms or cyano-groups, C₁₋₆ alkoxyl, C₁₋₆alkoxycarbonyl, carboxyl, cyano-group, nitryl, amino-group, —NR⁵—,methyl polyhalide, methoxyl polyhalide, methylthio polyhalide,—S(═O)_(p)R⁷, —NH—S(═O)_(p)R⁷, —C(═O)R⁷, —NHC(═O)H, —C(═O)NHNH₂,—NHC(═O)R⁷, —C(═NH)R⁷;

R⁵ represents hydrogen, C₁₋₆ alkycarbonyl, aryl, formoxyl, C₁₋₆ alkyl,C₁₋₆ alkoxycarbonyl;

X and Y are separately selected from —NR⁶—, —NH—NH—, —N═N—, —O—,—C(═O)—, C₁₋₄ alkanediyl, —CHOH—, —S—, —S(═O)p—, -X₁-C₁₋₄ alkanediyl- or—C₁₋₄ alkanediyl-X₁-, —CH(CN)—;

X₁ represents —NR⁶—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S(═O)p—;

R⁶ is separately selected from hydrogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl,C₁₋₆ alkoxyl or C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl.

R⁷ is selected from C₁₋₄ alkyl, amino-group-, —NH—NH—, mono- or di-(C₁₋₄alkyl) amino-group of C₁₋₄ alkyl polyhalide.

m is an integer from 0 to 5, n is an integer from 0 to 6;

P is an integer of 1 or 2.

In another preferred embodiment, the diaryl pyrimidine derivative hasthe structure shown as the formula II:

In another preferred embodiment, the diaryl pyrimidine derivative hasthe structure shown as the formula III:

The diaryl pyrimidine derivative or the pharmaceutically acceptablesalts thereof according to the present invention, the salts are selectedfrom hydrochloride, sulfate, tartrate, citrate, fumarate, or malate.

The second aspect of the present invention provides a diaryl benzopyrimidine derivative, N-oxides thereof, stereoisomerides, mixture ofstereoisomerides, or pharmaceutically acceptable salts, the diaryl benzopyrimidine derivative has the structure shown as the formula IV.

wherein R⁸ is independently selected from aryl, naphthyl, substitutednaphthyl, 5- or 6-membered aromatic heterocyclic, C₁₋₆ alkoxycarbonyl,aryloxycarbonyl, or substituted aryloxycarbonyl.

R⁹ and R¹⁰ respectively are separately selected from hydrogen, hydroxyl,halogen, C₁₋₆ alkoxyl, C₁₋₆ alkoxycarbonyl, carboxyl, cyano-group,nitryl, amino-group, —NR¹¹—, methyl polyhalide, methoxyl polyhalide,methylthio polyhalide, —S(═O)_(p)R¹², —NH—S(═O)_(p)R¹², —C(═O)R¹²,—NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹², —C(═NH)R¹².

Z and Y respectively are separately selected from —NR¹¹—, —NH—, —NH—NH—,—N═N—, —O—, —C(═O)—, C₁₋₄ alkanediyl, —CH(OH)—, —S—, —S(═O)p—, -X₂-C₁₋₄alkanediyl or -C₁₋₄ alkanediyl-X₂-, —CH(CN)—;

X₂ is selected from —NR¹¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CH(OH)—,—S(═O)p—;

R¹¹ is separately selected from hydrogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl,C₁₋₆ alkoxyl or C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl;

R¹² is selected from C₁₋₄ alkyl, amino-group, mono- or di-(C₁₋₄ alkyl)amino-group or C₁₋₄ alkyl polyhalide.

m is an integer from 0 to 5, n is an integer from 0 to 6;

P is an integer of 1 or 2.

The pharmaceutically acceptable salts of the diaryl benzo pyrimidinederivative according to the present invention, the pharmaceuticallyacceptable salts are selected from hydrochloride, sulfate, tartrate,citrate, fumarate, or malate.

The third aspect of the present invention provides a method forpreparing a diaryl pyrimidine derivative, comprising the followingsteps:

(a) 4-chloro benzo pyrimidine derivative, substituted phenol or aniline,and polar aprotic solvent are mixed together to react according to thefollowing general equation to obtain the diaryl benzo pyrimidinederivative;

or, the process comprises the steps of:

(i) 2-chloro benzo pyrimidine derivative and substituted phenol oraniline are heated to 150° C.-210° C. to fuse to react according to thefollowing general equation, to obtain the diaryl benzo pyrimidinederivative;

wherein, R⁸ is separately selected from aryl, substituted aryl,naphthyl, substituted naphthyl, 5- or 6-membered aromatic heterocyclic,C₁₋₆ alkoxycarbonyl, aryloxycarbonyl, or substituted aryloxycarbonyl.

R⁹ and R¹⁰ respectively are separately selected from hydrogen, hydroxyl,halogen, C₁₋₆ alkoxyl, C₁₋₆ alkoxycarbonyl, carboxyl, cyano-group,nitryl, amino-group, —NR¹¹—, methyl polyhalide, methoxyl polyhalide,methylthio polyhalide, —S(═O)_(p)R¹², —NH—S(═O)_(p)R¹², —C(═O)R¹²,—NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹², —C(═NH)R¹².

Z and Y respectively are separately selected from —NR¹¹—, —NH—, —NH—NH—,—N═N—, —O—, —C(═O)—, C₁₋₄ alkanediyl, —CH(OH)—, —S—, —S(═O)p—, -X₂-C₁₋₄alkanediyl or -C₁₋₄ alkanediyl-X₂-, —CH(CN)—;

X₂ is selected from —NR¹¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CH(OH)—,—S(═O)p—;

R¹¹ is separately selected from hydryogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl,C₁₋₆ alkoxyl or C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl;

R¹² is selected from C₁₋₄ alkyl, amino-group, mono- or di-(C₁₋₄ alkyl)amino-group or C₁₋₄ alkyl polyhalide.

m is an integer from 0 to 5, n is an integer from 0 to 6;

P is an integer of 1 or 2.

In another preferred embodiment, the reaction of step (a) is carried outunder the protection of inert gas; the inert gas is argon, nitrogen,helium, or combinations thereof.

In another preferred embodiment, the aprotic solvent used in step (a) isacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,tetrahydrofuran, or combinations thereof.

In another preferred embodiment, bases is added during the reaction ofstep (a); the base is potassium carbonate, sodium carbonate, cesiumcarbonate, sodium hydride, sodium hydroxide, or potassium hydroxide.

The fourth aspect of the present invention provides a pharmaceuticalcomposition; the pharmaceutical composition comprises effective dosageof diaryl pyrimidine derivative provided in the present invention or thepharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable carriers.

The fifth aspect of the present invention provides a pharmaceuticalcomposition; the pharmaceutical composition comprises effective dosageof diaryl benzo pyrimidine derivative provided in the present invention,N-oxides, stereoisomerides, mixture of stereoisomerides, orpharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable carriers.

The sixth aspect of the present invention provides a use of the diarylpyrimidine derivative provided in the present invention or thepharmaceutically acceptable salts thereof, for the manufacturing of amedicament for prevention or treatment of AIDS.

The seventh aspect of the present invention provides a use of the diarylbenzo pyrimidine derivative provided in the present invention, N-oxides,stereoisomerides, mixture of stereoisomerides, or pharmaceuticallyacceptable salts thereof, for the manufacturing of a medicament forprevention or treatment of AIDS.

Hereby, the present invention provides novel drugs to prevent or treatAIDS.

DETAILED DESCRIPTION OF THE INVENTION

Through intensive study, the inventor performed reorganization to thediaryl pyrimidine derivatives (DAPY), and simulated the action model andstructure-activity relationship of such kind of inhibitor with HIV-1 RT,by means of computer aided drug design, here by to guide furtherstructure improvement. Naphthyl group is introduced to C4-position ofpyrimidine ring, to strengthen the π-π accumulation between theinhibitor and the surrounding residues of amino acids, Tyr188, Tyr181,Trp229, and Tyr318. Meanwhile, substitutional groups are introduced toC5-, C6-positions of pyrimidine ring, to strengthen its synergisticeffect with naphthyl ring, and to disturb the catalytic function of thesurrounding residues of amino acids. A series of diaryl pyrimidinederivatives are prepared and the biological activities thereof aretested. The results showed that most of the compounds have strongactivities of anti HIV-1, and high selectivity index, and a part of thecompounds show good inhibition activity against drug-resistant viralstrain of L103N+Y181C.

The present invention provides a diaryl pyrimidine derivative orpharmaceutically acceptable salts thereof; the diaryl pyrimidinederivative has the structure shown as the formula I:

Preferably, the diaryl pyrimidine derivative provided in the presentinvention has the structure shown as the formula II:

wherein, -a¹=a²-a³=a⁴- represents the structure of a divalent freeradical: —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —N═N—CH═CH—,—N═CH—N═CH—, —N═CH—CH═N—;

-b¹=b²-b³=b⁴- represents the structure of a divalent free radical:—CH═CH—CH═CH—, —N═CH—CH═CH—, —N═N—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—;

R¹ and R² respectively are separately selected from hydrogen, hydroxyl,halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl, substitutedC₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl, amino-group, —NH(OH)—,—N(R⁶)p—;

R¹³ and R¹⁴ respectively are separately selected from hydrogen,hydroxyl, halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl,substituted C₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl,amino-group, —NH(OH)—, —N(R⁶)p—;

R¹³ and R¹⁴ respectively are separately selected from hydrogen,hydroxyl, halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl,substituted C₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl,amino-group, —NH(OH)—, —N(R⁶)p—;

R³ and R⁴ respectively are separately selected from hydrogen, hydroxyl,halogen, optionally C₁₋₄ alkyl substituted by cyano-group or —C(═O)R⁶,C₃₋₇ cycloalkyl, optionally C₂₋₆ alkenyl substituted by one or morehalogen atoms or cyano-groups, optionally C₂₋₆ alkynyl substituted byone or more halogen atoms or cyano-groups, C₁₋₆ alkoxyl, C₁₋₆alkoxycarbonyl, carboxyl, cyano-group, nitryl, amino-group, —NR⁵—,methyl polyhalide, methoxyl polyhalide, methylthio polyhalide,—S(═O)_(p)R⁷, —NH—S(═O)_(p)R⁷, —C(═O)R⁷, —NHC(═O)H, —C(═O)NHNH₂,—NHC(═O)R⁷, —C(═NH)R⁷;

R⁵ represents hydrogen, C₁₋₆ alkycarbonyl, aryl, formoxyl, C₁₋₆ alkyl,C₁₋₆ alkoxycarbonyl;

X and Y are separately selected from —NR⁶—, —NH—NH—, —N═N—, —O—,—C(═O)—, C₁₋₄ alkanediyl, —CHOH—, —S—, —S(═O)p—, -X₁-C₁₋₄ alkanediyl- or-C₁₋₄ alkanediyl-X₁-, —CH(CN)—;

X₁ represents —NR⁶—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S(═O)p—;

R⁶ is separately selected from hydrogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl,C₁₋₆ alkoxyl or C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl.

R⁷ is selected from C₁₋₄ alkyl, amino-group-, —NH—NH—, mono- or di-(C₁₋₄alkyl) amino-group of C₁₋₄ alkyl polyhalide.

m is an integer from 0 to 5, n is an integer from 0 to 6;

P is an integer of 1 or 2.

The method for preparing the compound shown as the formula II is asfollowing:

(1) A diaryl pyrimidine derivative wherein R¹ is H, Cl, C₁₋₄ alkyl, C₂₋₆alkynyl, C₂₋₆ alkenyl is prepared according to the reference(CN200710045937.0), and the general equation is as following:

(2) The diaryl pyrimidine derivative wherein R¹ is C₁₋₆ alkoxyl isprepared with the diaryl pyrimidine derivative substituted by Cl as thereactant to react with C₁₋₆ sodium alkoxide, the reaction equation is asfollowing:

(3) The diaryl pyrimidine derivative wherein R¹ is amino-group or—N(R⁶)p— (p=1,2) is prepared with the diaryl pyrimidine derivativesubstituted by Cl as reactant to react with alkanamine individually, thereaction equation is as following:

The compound shown as the formula II is an easily synthesized andcompletely novel anti-HIV reagent, and may be used as a candidateanti-HIV drug. The biological activity in the level of cells showedthat: (1) this type of compounds generally possess good anti-HIVactivity, and a part of the compounds not only show biological activityon nmol level, but also show high selectivity index. (2) Among thesynthesized compounds, a part of the compounds show good inhibitionactivity against drug-resistant viral strain of L103N+Y181C.

More preferably, the diaryl pyrimidine derivative synthesized in thepresent invention has the structure shown as the formula III:

wherein, R¹³ and R¹⁴ respectively are separately selected from hydrogen,hydroxyl, halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl,substituted C₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl,amino-group, —NH(OH)—, —N(R⁶)p—;

X is selected from —NR⁶—, —NH—NH—, —N═N—, —O—, —C(═O)—, C₁₋₄ alkanediyl,—CHOH—, —S—, —S(═O)p—, -X₁-C₁₋₄ alkanediyl- or -C₁₋₄ alkanediyl-X₁-,—CH(CN)—;

X₁ is selected from —NR⁶—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—,—S(═O)p—;

R⁶ is separately selected from hydrogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or alkycarboxyl, C₁₋₆alkoxyl or C₁₋₆ alkoxycarboxyl substituted by C₁₋₆ alkoxycarboxyl.

P is an integer of 1 or 2.

The method for preparing the compound shown as the formula III is asfollowing:

(1) R¹³ and R¹⁴ are H, Cl, C₁₋₄ alkyl, C₂₋₆ alkynyl, C₂₋₆ alkenylrespectively. The diaryl pyrimidine derivative, wherein X is O, isprepared according to the reference (CN200710045937.0); the generalreaction equation is as following:

i.e., under the protection of inert gas, substituted naphthol is addedto anhydrous aprotic solvent and agitated to dissolve, then 4-chloropyrimidine derivative is added and agitated to dissolve, after theaddition of anhydrous K₂CO₃, the temperature is controlled at 90˜100°C., the system is agitated to keep reaction for 8˜12 h. When TLC showsthat the reaction is complete, K₂CO₃ is filtered out, and the filtrateis poured into cold water, the crystal is filtered out and dried. Thedesired compound is achieved by recrystallization with toluene ordioxane and etc., or by column chromatography.

(2) R¹³ and R¹⁴ are H, Cl, C₁₋₄ alkyl, C₂₋₆ alkynyl, C₂₋₆ alkenylrespectively; the general reaction equation of preparing the diarylpyrimidine derivative wherein X is nitrogen is as following:

Substituted naphthylamine is dissolved in DMF, then 4-chloro pyrimidineis added and agitated to dissolve, and heated under reflux for 20 h inan oil bath at 150° C., the reaction mixture is poured into cold waterand the deposited solid is filtered out and dried. The desired compoundis obtained by recrystallization with toluene or dioxane and etc., or bycolumn chromatography.

The compound shown as the formula III is an easily synthesized andcompletely novel anti-HIV reagent, and may be used as a candidateanti-HIV drug. The biological activity in the level of cells showedthat: (1) this type of compounds generally possess good anti-HIVactivity, and a part of the compounds not only show biological activityon nmol level, but also show high selectivity index. (2) Among thesynthesized compounds, a part of the compounds show good inhibitionactivity against drug-resistant viral strain of L103N+Y181C.

Therefore, the present invention provides a pharmaceutical composition,the composition consists effective dosage of the diaryl pyrimidinederivative shown as the formula I, II, or III, or pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable carriers.

As used herein, the terms of “containing” or “comprising” comprise“including”, “basically be consisted of”, and “be consisted of”.

As used herein, the components of the term of “pharmaceuticallyacceptable” or “bromatologically acceptable” are those suitable to humanand/or animals without excess adverse-effect (such as toxicity, irritantand allergic reaction), i.e. the substances possessing reasonable ratioof benefits and risk.

As used herein, the term of “effective dosage” refers to the amount thatis sufficient to achieve the desired function or activity on humanand/or animal and can be accepted by human and/or animal.

As used herein, the term of “pharmaceutically acceptable carriers”refers to the carriers of medicaments, including all kinds of excipientsand diluents. The term refers to such kinds of carriers: they are notnecessary active components, and possessing no excess toxicity afterapplication. Suitable carriers are well known to those skilled in theart. Full discussion on pharmaceutically acceptable carriers can befound in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991).The pharmaceutically acceptable carriers used in the pharmaceuticalcompositions can be liquid, such as water, brine, glycerol and alcohol.Additionally, auxiliary substances can be existed in the carriers, suchas fillers, disintegrating agents, lubricants, flow aids, effervescentagents, wetting agents or emulsifiers, corrigents, pH buffer substancesand etc.

The present invention provides a diaryl benzo pyrimidine derivative,N-oxides, stereoisomerides, mixture of stereoisomerides, orpharmaceutically acceptable salts thereof, the diaryl benzo pyrimidinederivative has the structure shown as the formula IV:

wherein R⁸ is independently selected from aryl, substituted aryl,naphthyl, substituted naphthyl, 5- or 6-membered aromatic heterocyclic,C₁₋₆ alkoxycarbonyl, aryloxycarbonyl, or substituted aryloxycarbonyl;

R⁹ and R¹⁰ respectively are separately selected from hydrogen, hydroxyl,halogen, C₁₋₆ alkoxyl, C₁₋₆ alkoxycarbonyl, carboxyl, cyano-group,nitryl, amino-group, —NR¹¹—, methyl polyhalide, methoxyl polyhalide,methylthio polyhalide, —S(═O)_(p)R¹², —NH—S(═O)_(p)R¹², —C(═O)R¹²,—NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹², —C(═NH)R¹²;

Z and Y respectively are separately selected from —NR¹¹—, —NH—, —NH—NH—,—N═N—, —O—, —C(═O)—, C₁₋₄ alkanediyl, —CH(OH)—, —S—, —S(═O)p—, -X₂-C₁₋₄alkanediyl or -C₁₋₄ alkanediyl-X₂-, —CH(CN)—;

X₂ is selected from —NR¹¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CH(OH)—,—S(═O)p—;

R¹¹ is separately selected from hydrogen, aryl, formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted byformoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl,C₁₋₆ alkoxyl or C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl;

R¹² is selected from C₁₋₄ alkyl, amino-group, mono- or di-(C₁₋₄ alkyl)amino-group or C₁₋₄ alkyl polyhalide;

m is an integer from 0 to 5, n is an integer from 0 to 6;

P is an integer of 1 or 2.

The method for preparing the compound shown as the formula III is asfollowing:

Method One:

4-chloro benzo pyrimidine derivative is reacted with the correspondingsubstituted phenol (or phenylamine and etc.) under the exsistence ofK₂CO₃ to obtain the product of the present invention, the generalreaction equation is as following:

The detailed steps are as following: under the protection of inert gas,substituted phenol (or phenylamine and etc.) is added to anhydrousaprotic solvent and agitated to dissolve, then 4-chloro benzo pyrimidinederivative is added and agitated to dissolve, after the addition ofanhydrous potassium carbonate, the system is agitated to keep reactionfor 8˜12 h at 80˜120° C. When TLC shows that the reaction is complete,K₂CO₃ is filtered out, and the filtrate is poured into cold water, thecrystal is filtered out and dried. The desired compound is obtainedthrough decoloring by activated carbon and recrystallization withtoluene.

More preferably, the molar ratio of 4-chloro benzo pyrimidine derivativeand substituted phenol (or phenylamine and etc.) is 1:1.2˜1:1.5.Anhydrous K₂CO₃ should be greatly excess, approximately be 5 times ofthe amount of substituted phenol; the aprotic solvent is DMF, DEA,acetonitrile; 1 mmol 4-chloro benzo pyrimidine derivative needs 6˜8 mLaprotic solvent; the inert gas is nitrogen, argon and etc.

Method Two:

2-chloro benzo pyrimidine derivative is reacted with the correspondingsubstituted phenol (or phenylamine and etc.) in solvent-free conditionsto obtain the product of the present invention; the general reactionequation is as following:

The detailed steps are as following: substituted phenol (or phenylamineand etc.) are mixed together, and heated to 150° C.-210° C. until thereactants are completely fused, and kept reaction for 1 h. When TLCshows that the reaction is complete, the reaction mixture is dissolvedin DMF, decolored with activated carbon, and filtered, the filtrate ispoured into cold water. The solid is filtered out and dried. The desiredcompound is obtained through recrystallization with toluene.

The compound shown as the formula IV is an easily synthesized andcompletely novel anti-HIV reagent, and may be used as a candidateanti-HIV drug. The biological activity in the level of cells showedthat: this type of compounds generally possesses good anti-HIV activity,and a part of the compounds not only show biological activity on nmollevel, but also show high selectivity index.

Therefore, the present invention provides a pharmaceutical composition,the composition comprises effective amount of the diaryl benzopyrimidine derivative shown as the formula IV, N-oxides,stereoisomerides, mixture of stereoisomerides, or pharmaceuticallyacceptable salts therefore; and pharmaceutically acceptable carriers.

The characteristics mentioned in the present invention or in theembodiments can be free to combine.

The main benefits of the present invention are as follows:

1. The compound provided in the present invention possesses novelstructure, and good anti HIV biological activity, and slight celltoxicity.

2. The preparation method of the compound provided in the presentinvention is easy, and can be further developed as anti-AIDS drugs.

The present invention will be further explained in respect of thevarious embodiments below. It is to be understood that the embodimentsserve to explain only, without limitation the scope of the presentinvention. The experimental processes of the following embodiments wherethe conditions are not listed should be carried out generally accordingto the regular conditions or according to the suggested conditions bymanufacturers. Unless specifically stated to the contrary, percents,ratios, proportions, or parts herein are all by weight.

The units of the weight volume percent herein are familiar to thoseskilled in the art, such as applied to refer to the weight of the solutein 100 mL solution.

Unless specifically defined to the contrary, all the specialized orscientific terms herein possess the same meaning as that known to thoseskilled in the art. Additionally, any process or material similar orequivalent to the records can be applied in the process of the presentinvention. The preferred embodiments and materials herein serve todemonstrate only.

Anti-HIV Biological Activity Test in the Embodiments of the PresentInvention

Anti-virus activity of cells in vitro was determined by Rega Institutefor Medical of Spain Katholleke University, consisting mainly:inhibitory activity towards HIV-infected MT-4 cells and cell toxicity.The method is described below: exert the compound on the HIV-infectedME-4 cells, and determine the protection of the drug on the cell lesionsinduced by HIV at varied HIV-infection intervals, calculate the halfeffective concentration IC₅₀, the required concentration that protect50% of cells from cell lesions induced by HIV. Toxicity determination iscarried out in parallel with anti-HIV activity experiments, also in thecultured MT-4 cells, determine the CC₅₀, the concentration that leads50% of uninfected cells to cell lesions, and calculate the selectivityindex SI=CC₅₀/IC₅₀ with the MTT method.

Materials and Methods

Anti-HIV activity of various compounds is monitored by the inhibitoryefficiency of drugs on the cell lesions induced by HIV. Carry out cellculture with MT-4 cells. The adopted virus strains are HIV-1 IIIB strainand drug-resistant viral strain of L103N+Y181C.

The detailed operation is as follows: the compound is dissolved withDMSO or water and diluted with phosphate buffer saline, 3×10⁵ MT-4 cellsare cultured with 100 μL various concentrations of compounds for 1 h,then 100 μL suitable virus dilution is added to the compound, and thecells are cultured at 37° C. for 1 h. After being washed for 3 times,the cells are suspended again in the culture media containing or notcompounds individually. Subsequently, the cells are transferred to theatmosphere containing 5% CO₂ and cultured for 7 days at 37° C., andculture media containing or not compounds are used to replace orsupplement the culture solution on the third day after infection. Kindsof culture conditions should be duplicated. The cell lesions caused byvirus are monitored with reverse light microscopy everyday. Typically,the virus dilution applied in the present experiments generally causecell lesion on the fifth day after infection. Inhibitory concentrationof a drug is expressed with the concentration that is required for 50%inhibition of cell lesions (EC₅₀) caused by virus and meanwhile shows nodirect toxicity to cells (CC₅₀). It should be emphasized that, when thecompound is poorly water-soluble and can only be dissolved in DMSO, theratio of DMSO to water is generally below 10% (the final concentrationof DMSO in MT-4 cell culture media is smaller than 2%). Because DMSO caninfluence the anti-virus activity of the tested compounds, blank testson the solution containing the same concentration of DMSO should beconducted in parallel. Additionally, the final concentration of DMSO isfar below the concentration required to influence the replication ofHIV-1 in T cells.

Example 1 Synthesis of the Diaryl Pyrimidine

Under the protection of inert gas, naphthol was added to anhydrousaprotic solvent, and agitated to dwassolve, then 4-chloro pyrimidinederivative was added and agitated to dissolve, after addition ofanhydrous K₂CO₃, the temperature was controlled at 90˜100° C. and thesystem was agitated to keep reaction for 8˜12 h. When TLC shows that thereaction was complete, K₂CO₃ was filtered out, and the filtrate waspoured into cold water, the deposited crystal was filtered out anddried. The desired compound was obtained through decoloring by activatedcarbon and recrystallization with toluene.

Target compounds were prepared by the above mentioned process withvarious 4-chloro pyrimidine derivatives and various substitutednaphthols, parts of the results are as follows:

Under the protection of N₂, 8-hydroxy quinoline (4.2 mmol) was added to30 mL anhydrous DMF and agitated to dissolve, then2-(4-cyanoanilino)-4-chloro methyl pyrimidine (3.5 mmol) was added andagitated for 10 min to dissolve, after addition of anhydrous K₂CO₃(0.021 mol), the temperature was controlled at 80° C. and the system wasagitated to keep reaction for 8 h. When TLC shows that the reaction wascomplete, K₂CO₃ was filtered out, and the filtrate was poured into 300mL cold water, solid was deposited; the solid was filtered out and driedand the crude product was prepared. The desired compound 1 was achievedthrough decoloring by activated carbon and recrystallization withtoluene.

Brown powder, yield: 87%: mp: 178.6-181.5° C.; ¹HNMR(DMSO, 400 MHz)δ_(ppm): 6.74(d, J=5.6Hz, 1H, CH), 7.21-7.28(m, 4H, Ph), 7.57-8.83(m,6H, Quin), 8.45(d, J=5.6Hz, 1H, CH), 9.98(s, 1H, NH).

Under the protection of N₂, 8-hydroxy quinoline (5.2 mmol) was added to30 mL anhydrous acetonitrile and agitated to dissolve, then2-(4-Cyanoanilino)-4,6-dichloro pyrimidine (5.2 mmol) was added andagitated for 10 min to dwassolve, after addition of anhydrous K₂CO₃(0.021 mol), the temperature was controlled at 90˜100° C. and the systemwas agitated to keep reaction for 8 h. When TLC shows that the reactionwas complete, K₂CO₃ was filtered out, and the filtrate was poured into300 mL cold water, solid was deposited; the solid was filtered out anddried and the crude product was prepared. The desired compound 2 wasachieved through decoloring by activated carbon and recrystallizationwith toluene.

Green powder, yield: 85%; mp:138.4-141.4° C.; ¹HNMR(DMSO, 400 MHz)δ_(ppm): 6.92(s, 1H, CH), 7.06-7.24(m, 4H, Ph), 7.55-8.82(m, 6H, Quin),10.33(s, 1H, NH).

The prepared compound 2 (2 mmol) above was dissolve in 25 mL dioxane,and agitated to dissolve, then 5 mL methylamine alcohol solution wasadded, and the temperature was controlled at 140-150° C., and the systemwas agitated to keep reaction for 12 h. When TLC shows that the reactionwas complete, compound 3 was achieved by recrystallization with water.

White powder, yield: 68%, mp: 231.4-232.1° C.; ¹HNMR(DMSO, 400 MHz)δ_(ppm): 2.82(s, 3H, NHCH₃), 5.50(s, 1H, CH), 7.20 (s, 1H, NHCH₃),7.34-7.79 (m, 4H, Ph), 7.48-8.72(m, 6H, Quin), 9.46(s, 1H, NH).

Sodium (10 mmol) was dissolved in 50 mL anhydrous methol, and agitatedto dissolve, then the prepared compound 2 was added, and the temperaturewas controlled at 40-50° C., the system was agitated to keep reactionfor 48 h. When TLC shows that the reaction was complete, compound 4 wasachieved by recrystallization with water.

White powder, yield: 92%; mp: 231.4-232.1° C.; ¹HNMR(DMSO, 400 MHz)δ_(ppm): 3.92(s, 3H, OCH₃), 6.02(s, 1H, CH), 7.17-7.32(m, 4H, Ph),7.54-8.82(m, 6H, Quin), 9.87(s, 1H, NH).

Example 2 Synthesis of the Diaryl Pyrimidine Derivative

Under the protection of inert gas, substituted naphthol was added toanhydrous aprotic solvent, and agitated to dissolve, then 4-chloropyrimidine derivative was added and agitated to dissolve, after additionof anhydrous K₂CO₃, the temperature was controlled at 90˜100° C., thesystem was agitated to keep reaction for 8˜12 h. When TLC shows that thereaction was complete, K₂CO₃ was filtered out, and the filtrate waspoured into 300 mL cold water, solid was deposited; the solid wasfiltered out and dried. The desired compound was obtained through columnchromatography or recrystallization.

Target compounds were prepared by the above mentioned process with4-chloro pyrimidine derivatives and various substituted naphthols; partsof the results are as following:

Under the protection of N₂, β-naphthol derivative (4.2 mmol) was addedto 30 mL anhydrous DMF, and agitated to dissolve, then2-(4-Cyanoanilino)-4-methyl pyrimidine (3.5 mmol) is added and agitatedfor 10 min to dissolve, after addition of anhydrous K₂CO₃, thetemperature is controlled at 90˜100° C., the system was agitated to keepreaction for 8 h. When TLC shows that the reaction was complete, thefiltrate was poured into 300 mL cold water, solid was deposited; thesolid was filtered out and dried and the crude product was prepared. Thedesired compound 20 was achieved through column separation.

White powder, yield: 89.3%; mp 249.2-250.1° C.;¹H NMR (400 MHz, DMSO-d₆)δ 3.90 (s, 3H, CH₃), 6.76 (d, 1H, J=4.0 Hz, CH), 7.25-7.55 (m, 4H, Ph),7.64-8.50 (m, 5H, Naph), 8.71 (s, 1H, CH), 10.10 (s, 1H, NH); ¹³C NMR(400 MHz, DMSO-d₆) δ 61.77, 99.70, 102.55, 108.66, 118.22, 118.99,119.27, 123.33, 125.13, 126.97, 129.96, 131.14, 132.42, 143.19, 144.35,146.29, 158.98, 160.42, 168.97. MS (EI) m/z: 393.1 (M+); Anal.(C₂₃H₁₅N₆O₂) C, H, N.

White powder, yield: 41.8%; mp 249.3-250.4° C.; ¹H NMR (400 MHz,DMSO-d₆)δ 3.85 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃), 6.78 (d, J=4.0Hz, 1H),7.24-7.52 (m, 4H, Ph), 7.54-8.54 (m, 4H, Naph), 8.49 (d, J=4.0Hz, 1H);¹³C NMR (400 MHz, DMSO-d₆) δ 56.83, 62.23, 99.77, 102.98, 104.10,109.61, 118.62, 119.63, 119.76, 123.76, 125.20, 125.46, 131.61, 132.93,133.28, 135.82, 144.87, 148.00, 153.19, 160.83, 169.18. MS (EI) m/z:423.2 (M+); Anal. (C₂₄H₁₇N₅O₃) C, H, N.

White powder, yield: 85.9%, mp 253.2-254.8 □C;¹H NMR (400 MHz, DMSO-d₆)δ 12 ¹³C NMR (400 MHz, DMSO-d₆) δ 3.83 (s, 3H, OCH₃), 6.69 (d, J=5.6Hz,¹H), 7.28-7.67 (m, 4H, Ph), 7.54-8.52 (m, 5H, Naph), 8.45 (d, J=5.6Hz,1H), 10, 07 (s, 1H, NH); ¹³C NMR (400 MHz, DMSO-d₆) δ 56.63, 99.94,102.97, 108.98, 109.02, 118.66, 119.79, 119.81, 121.34, 125.39, 129.25,130.47. 131.98, 132.98, 133.04, 144.47, 144.92, 152.33, 159.40. 160.67,169.56. MS (EI) m/z: 393.1 (M+); Anal. (C₂₃H₁₅N₆O₂) C, H, N.

White powder, yield: 71.6%, mp 297.5-298.7 □C;¹H NMR (400 MHz, DMSO-d₆)δ 6.82 (d, J=4.0Hz, 1H), 7.27-7.52 (m, 4H, Ph), 8.02-8.54 (m, 5H, Naph),8.82 (s, 1H, CH), 10.12 (s, 1H, NH); ¹³C NMR (400 MHz, DMSO-d₆) δ100.18, 103.15, 109.78, 118.81, 119.09, 119.72, 123.09, 125.27, 125.55,129.19, 130.08, 131.49, 132.81, 132.93, 135.93, 144.72, 159.33, 161.18,168.88. MS (EI) m/z: 393.1 (M+); Anal. (C₂₂H₁₂ClN₅O) C, H, N, Cl.

White powder, yield: 33.4%, mp: 268.4-269.2 □C;¹H NMR (400 MHz, DMSO-d₆)δ 12 ¹³C NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 3H, CH₃), 6.82 (d, J=4.4Hz,1H), 7.25-7.49 (m, 4H, Ph), 7.82-8.63 (m, 4H, Naph), 8.52 (d, J=4.4Hz,1H), 10.11 (s, 1H, NH); ¹³C NMR (400 MHz, DMSO-d₆) δ 57.21, 99.71,103.15, 108.27, 110.23, 118.66, 119.25, 119.72, 124.69, 125.54, 126.74,127.57, 131.95, 132.94, 133.76, 141.45, 144.75, 152.66, 159.35, 161.13,168.47. MS (EI) m/z: 427.1 (M+); Anal. (C₂₃H14ClN₅O2) C, H, N, Cl.

Example 3-1 Synthesis of the Diaryl Benzo Pyrimidine Derivative (MethodOne)

Under the protection of inert gas, substituted phenol (or phenylamineand etc.) is added to aprotic solvent, and agitated to dissolve, andthen 4-choloro benzo pyrimidine derivative is added and agitated todissolve, after addition of anhydrous K₂CO₃, the temperature iscontrolled at 80˜120° C. and the system was agitated to keep reactionfor 8˜12 h. When TLC shows that the reaction was complete, K₂CO₃ wasfiltered out, and the filtrate was poured into cold water, the depositedcrystal was filtered out and dried. The desired compound was obtainedthrough decoloring by activated carbon and recrystallization withtoluene.

Target compounds were prepared by the above mentioned process withvarious 4-chloro pyrimidine derivatives and various substituted phenols,parts of the results are as following:

Under the protection of N₂, 2-methylphenol (4.2 mmol) was added to 30 mLanhydrous DMF, and agitated to dissolve, then2-(4-Cyanoanilino)-4-chloro benzo pyrimidine (3.5 mmol) was added andagitated to dissolve, after addition of anhydrous K₂CO₃ (0.021 mol), thetemperature was controlled at 90˜100° C. and the system was agitated tokeep reaction for 8 h. When TLC shows that the reaction was complete,K₂CO₃ was filtered out, and the filtrate was poured into 300 mL coldwater, solid was deposited; the solid was filtered out and dried. Thedesired compound was obtained through decoloring by activated carbon andrecrystallization with toluene.

Brown powder, yield: 75% ; mp; 197.3-197.4° C.; ¹HNMR (DMSO-d₆) δ (ppm)2.16 (s, 3H, CH₃), 7.30-7.44 (m, 4H, Ar′H), 7.49 (td, 1H, J=7.6 Hz,J′=1.2 Hz, ArH₇), 7.56 (d, 2H, J=8.8 Hz, Ar″H_(2,6)), 7.72 (d, 1H, J=8.4Hz, ArH₆), 7.86 (d, 2H, J=8.8 Hz, Ar″H_(3,5)), 7.90 (td, 1H, J=7.6 Hz,J′=1.2 Hz, ArH₈), 8.27 (dd, 1H, J=8.0 Hz, J′=0.8 Hz, ArH₉), 10.04 (s,1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 16.4 (CH₃), 102.8 (Ar″C₄), 112.2 (ArC₅), 118.9(2C, Ar″C_(2,6)), 120.0 (CN), 122.9 (ArC₆), 124.2 (Ar′C₆), 124.8 (ArC₇),125.9 (ArC₉), 126.7 (Ar′C₄), 128.0 (Ar′C₅), 130.7 (Ar′C₃), 131.9 (ArC₈),133.1 (Ar′C₂), 135.4 (2C, Ar″C_(3,5)), 145.4 (Ar″C₁), 151.4 (Ar′C₁),153.1 (ArC₁₀), 155.7 (ArC₂), 167.2 (ArC₄).

MS (ESI) m/z 353 (M⁺+1).

The operation was the same as above mentioned. Yellow acicular crystal,yield: 85%; mp: 267.3-267.6° C.; ¹H NMR (DMSO-d₆) δ (ppm) 7.41 (d, 2H,J=6.8 Hz, Ar″H_(2,6)), 7.47 (t, 1H, J=7.2 Hz, ArH₇), 7.61 (d, 2H, J=8.8Hz, Ar′H_(2,6)), 7.71-7.75 (m, 3H, ArH₆+Ar″H_(3,5)), 7.88 (td, 1H, J=8.4Hz, J′=1.2 Hz, ArH₈), 7.94 (d, 2H, J=8.4 Hz, Ar′H_(3,5)), 8.21 (d, 1H,J=8.4 Hz, ArH₉), 10.02 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 103.0 (Ar″C₄), 112.5 (ArC₅), 118.8 (2C,Ar″C_(2,6)), 119.0 (2C, Ar′C_(2,6)), 120.0 (CN), 124.2 (Ar′C₄), 124.8(ArC₆), 125.2 (2C, Ar′C_(3,5)), 126.0 (ArC₇), 133.1 (ArC₉), 133.2 (2C,Ar″C_(3,5)), 135.5 (ArC₈), 145.3 (Ar″C₁), 152.2 (ArC₁₀), 153.1 (Ar′C₁),155.4 (ArC₂), 167.4 (ArC₄).

MS (ESI) m/z 417 (M⁺+1).

The operation was the same as above mentioned. White acicular crystalsolid, yield: 98.3%; mp:219.7-220.3° C.; ¹H NMR (DMSO-d₆) δ (ppm) 2.39(s, 3H, CH₃), 7.18-7.22 (m, 3H, Ar′H), 7.43 (d, 1H, J=7.6 Hz, Ar′H),7.48 (td, 1H, J=8.0 Hz, J′=1.2 Hz, ArH₇), 7.59 (d, 2H, J=8.4 Hz,Ar″H_(2,6)), 7.72 (d, 1H, J=8.4 Hz, ArH₆), 7.88 (td, 1H, J=7.2 Hz,J′=1.2 Hz, ArH₈), 7.93 (d, 2H, J=8.4 Hz, Ar″H_(3,5)), 8.22 (dd, 1H,J=8.4 Hz, J′=1.2 Hz, ArH₉), 10.03 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 20.8 (CH₃), 102.3 (Ar″C₄), 112.0 (ArC₅), 118.4(2C, Ar″C_(2,6)), 119.0 (CN), 119.4 (ArC₆), 122.4 (Ar′C₆), 123.6(Ar′C₂), 124.1 (ArC₇), 125.3 (ArC₉), 126.5 (Ar′C₄), 129.5 (Ar′C₅), 132.6(2C, Ar″C_(3,5)), 134.8 (ArC₈), 139.6 (Ar′C₃), 144.8 (Ar″C₁), 152.3(ArC₁₀), 152.5 (Ar′C₁), 155.0 (ArC₂), 167.1 (ArC₄).

MS (ESI) m/z 353 (M⁺+1).

The operation was the same as above mentioned. White flocculus solid,yield:89.1%; mp: 218.2-218.4° C.; ¹H NMR (DMSO-d₆) δ (ppm) 3.83 (s, 3H,CH₃O), 7.08 (d, 2H, J=6.8 Hz, Ar′H_(3,5)), 7.32 (d, 2H, J=6.8 Hz,Ar′H_(2,6)), 7.47 (td, 1H, J=8.0 Hz, J′=0.8 Hz, ArH₇), 7.59 (d, 2H,J=8.8 Hz, Ar″H_(2,6)), 7.71 (d, 1H, J=8.4 Hz, ArH₆), 7.87 (td, 1H, J=8.4Hz, J′=1.2 Hz, ArH₈), 7.95 (d, 2H, J=8.4 Hz, Ar″H_(3,5)), 8.21 (dd, 1H,J=8.4 Hz, J′=1.2 Hz, ArH₉), 9.99 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 56.0 (CH₃O), 102.9 (Ar″C₄), 112.6 (ArC₅),115.3 (2C, Ar′C_(3,5)), 119.0 (2C, Ar″C_(2,6)), 120.1 (CN), 123.5 (2C,Ar′C_(2,6)), 124.2 (ArC₆), 124.7 (ArC₇), 125.9 (ArC₉), 133.2 (ArC₈),135.3 (2C, Ar″C_(3,5)), 145.4 (Ar″C₁), 146.2 (Ar′C₁), 153.0 (ArC₁₀),155.6 (Ar′C₄), 157.6 (ArC₂), 167.9 (ArC₄).

MS (ESI) m/z 369 (M⁺+1).

Example 3-2 Synthesis of the Diaryl Benzo Pyrimidine Derivative (MethodTwo)

2-methoxyphenol and 2-chloro benzo pyrimidine derivative were mixedtogether, and heated to 150˜210° C. until the reactants melt completely,and frit reaction lasts for 1 h. When the TLC demonstrates that thereaction was complete, the reaction mixture was dissolved into DMF,decolored with activated carbon and filtered, the filtration was pouredinto cold water; the deposited solid was filtered out and dried. Thedesired compound was obtained through recrystallization with toluene.

White flocculus solid, yield: 82.9%; mp: 220.0-220.5° C.; ¹H NMR(DMSO-d₆) δ (ppm) 3.73 (s, 3H, CH₃O), 7.10 (td, 1H, J=7.6 Hz, J′=1.6 Hz,Ar′H₆), 7.30 (dd, 1H, J=8.4 Hz, J′=1.2 Hz, Ar′H₃), 7.35-7.41 (m, 2H,Ar′H_(4,5)), 7.47 (td, 1H, J=8.0 Hz, J′=0.8 Hz, ArH₇), 7.56 (d, 2H,J=8.8 Hz, Ar″H_(2,6)), 7.71 (d, 1H, J=8.4 Hz, ArH₆), 7.84 (d, 2H, J=8.8Hz, Ar″H_(3,5)), 7.89 (td, 1H, J=8.4 Hz, J′=1.2 Hz, ArH₈), 8.22 (d, 1H,J=8.4 Hz, ArH₉), 10.06 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 55.8 (CH₃O), 102.3 (Ar″C₄), 111.6 (ArC₅),113.4 (Ar′C₃), 118.3 (2C, Ar″C_(2,6)), 119.5 (CN), 121.0 (ArC₆), 123.1(Ar′C₅), 123.8 (ArC₇), 124.2 (Ar′C₆), 125.4 (ArC₉), 127.2 (Ar′C₄), 132.6(2C, Ar″C_(3,5)), 134.9 (ArC₈), 140.9 (Ar″C₁), 144.9 (Ar′C₁), 151.1(ArC₁₀), 152.6 (Ar′C₂), 155.2 (ArC₂), 166.8 (ArC₄).

MS (ESI) m/z 367 (M⁺−1).

The operation was the same as above mentioned. White powder, yield:89.6%; mp: 230.7-231.9° C.; ¹H NMR (DMSO-d₆) δ (ppm) 7.38-7.43 (m, 3H,Ar″H_(2,6)+Ar′H₄), 7.48 (t, 1H, J=7.6 Hz, ArH₇), 7.55-7.59 (m, 4H,Ar′H_(3,5)+Ar′H_(2,6)), 7.72 (d, 1H, J=8.0 Hz, ArH₆), 7.87-7.91 (m, 3H,Ar″H_(3,5)+ArH₈), 8.23 (d, 1H, J=8.0 Hz, ArH₉), 10.04 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 102.3 (Ar″C₄), 112.0 (ArC₅), 118.5 (2C,Ar″C_(2,6)), 119.5 (CN), 122.2 (2C, Ar′C_(2,6)), 123.7 (ArC₆), 124.2(ArC₇), 125.4 (Ar′C₄), 126.0 (ArC₉), 129.9 (2C, Ar′C_(3,5)), 132.6 (2C,Ar″C_(3,5)), 134.9 (ArC₈), 144.8 (Ar″C₁), 152.4 (ArC₁₀), 152.6 (Ar′C₁),155.1 (ArC₂), 167.2 (ArC₄).

MS (ESI) m/z 337 (M⁺−1).

The operation was the same as above mentioned. White flocculus solid,yield: 86.6%; mp: 220.6-220.8° C.; ¹H NMR (DMSO-d₆) δ (ppm) 2.39 (s, 3H,CH₃), 7.26 (d, 2H, J=8.8 Hz, Ar″H_(2,6)), 7.33 (d, 2H, J=8.4 Hz,Ar′H_(3,5)), 7.46 (t, 1H, J=8.0 Hz, ArH₇), 7.58 (d, 2H, J=8.4 Hz,Ar′H_(2,6)), 7.70 (d, 1H, J=8.4 Hz, ArH₆), 7.87 (td, 1H, J=8.0 Hz,J′=1.6 Hz, ArH₈), 7.94 (d, 2H, J=8.8 Hz, Ar″H_(3,5)), 8.20 (dd, 1H,J=8.4 Hz, J′=0.8 Hz, ArH₉), 9.98 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 20.5 (CH₃), 102.4 (Ar″C₄), 112.1 (ArC₅), 118.5(2C, Ar″C_(2,6)), 119.5 (CN), 121.8 (2C, Ar′C_(2,6)), 123.7 (ArC₆),124.2 (ArC₇), 125.4 (ArC9), 130.2 (2C, Ar′C_(3,5)), 132.6 (2C,Ar″C_(3,5)), 134.8 (ArC₈), 135.1 (Ar′C₄), 144.9 (Ar″C₁), 150.1 (ArC₁₀),152.5 (Ar′C₁), 155.1 (ArC₂), 167.2 (ArC₄).

MS (ESI) m/z 351 (M⁺−1).

The operation was the same as above mentioned. Yellow acicular solid,yield: 79.4%; mp: 218.6-220.2° C.; ¹HNMR (DMSO-d₆) δ (ppm) 2.20 (s, 3H,CH₃), 7.51 (t, 1H, J=7.6 Hz, ArH₇), 7.61 (d, 2H, J=8.8 Hz, Ar″H_(2,6)),7.73-7,76 (m, 2H, Ar′H₅+ArH₆), 7.88-7.94 (m, 4H, ArH₈+Ar′H₅+Ar″H_(3,5)),8.27 (d, 1H, J=8.0 Hz, ArH₉), 10.09 (s, 1H, NH).

¹³C NMR (DMSO-d₆) δ (ppm) 16.3 (CH₃), 102.6 (Ar″C₄), 111.2 (ArC₅), 117.6(Ar′C4), 118.5 (2C, Ar″C_(2,6)), 118.9 (CN), 119.5 (ArC₆), 123.6(Ar′C₂), 124.5 (ArC₇), 125.6 (ArC₉), 132.7 (ArC₈), 132.8 (2C,Ar″C_(3,5)), 133.3 (Ar′C₃), 135.3 (Ar′C₅), 135.5 (Ar′C₆), 144.7 (Ar″C₁),147.6 (ArC₁₀), 152.8 (Ar′C₁), 154.9 (ArC2), 165.2 (ArC₄).

MS (ESI) m/z 511 (M⁺+1).

Effect Example 1 Anti HIV Biological Activity Test

NVP, DLV and EFV were used as control substances, the inhibitoryactivities of part of the target compounds are shown in Table 1.

TABLE 1 Anti-HIV activities and cell toxicities of Compounds 1-32 onMT-4 cells EC50 HIV-1(IIIB) 103N + 181C CC₅₀ Compounds R1 R2 R4 (nM)(μM) (μM) SI^(b) 1 H H 2.9 38.84 38.84 13393 2 Cl H 19.5 20.11 20.101031 3 NHCH3 H 8.9 54.20 54.19 6089 4 OCH3 H 12.8 42.23 42.23 3299 5 HMe 5.8 19.91 19.91 3432 6 Cl Me 25.7 44.72 44.72 1740 7 NHCH3 Me 15.836.53 36.53 2312 8 OCH3 Me 17.8 31.82 31.81 1787 9 Cl i-Pr 6-CN 50.03.36 435.55 8711 10 H H 1-Me 3.46 11.00 114.11 32981 11 H H 3-Me2.3 >70.94 71.16 30941 12 H H 1,3-diMe 4.1 1.17 313.39 76436 13 H H1,6-diBr 4.6 >50.39 51.06 11099 14 H H 6-CN 3.3 6.30 67.81 20548 15 H H1-Br-6-CN 1.6 0.24 290.00 181247 16 H H 3-Br-6-CN 1.1 >56.53 55.39 5035717 NHCH3 Me 1-Br 15.4 6.15 177.01 11494 18 NHCH3 Et 1-Br-6-CN 6.2 >59.52303.92 49020 19 NHCH3 i-Pr 6-CN 7.6 4.58 265.00 34868 NVP 75.1 —5.41 >72 DLV 72 — 0.86 12 EFV 3 560 4.30 >1434 ^(a)IC₅₀: theconcentration of an inhibitor that is required for 50% inhibition ofHIV-1 RT; ^(b)SI: Selectivity index, the ratio of CC₅₀/IC₅₀.

The results show that the compounds included by the general chemicalformula possess strong anti HIV-1 virus activity, slight cell toxicityand high selectivity index; and a part of the compounds also exhibitcertain anti HIV-2 action, this is different from the classical NNRTIs.

Effect Example 2 Anti HIV-1 Biological Activity Test

Screening for in vitro activity of anti HIV-1 reverse transcriptase(HIV-1 RT) (tested by The National Center for Drug Screening), thematerials and methods were as following:

-   1. HIV-1 RT: Extracted in the lab and stored.-   2. Sample treatment: sample was dissolved in DMSO to achieve    suitable concentration before use, and 10-fold diluted with double    distilled water, 8 dilution degrees per sample (sample was not    dissolved completely in double distilled water).-   3. Positive control medicine: nevirapine (NVP), Nanjing Zezhong    Medical & Chemical Information Research Center.-   4. Test method: after dilution, the sample was added to the reaction    buffer containing Biotin-dUTP and genetically engineered target    enzyme to incubate under optimal reaction conditions, avidin labeled    horseradish peroxidase system was used as colour reagent, and the    value of OD450 was determined.

The inhibitory activities of parts of target compounds are shown inTable 2.

TABLE 2 Biological activities of the compounds to wild type, mutant typeHIV-1 and HIV-1 RT EC50^(b) WT(IIIB) 103N + 181C CC₅₀ Compounds R13 R14X IC₅₀ ^(a) (ug/ml) (nM) (nM) (μM) SI^(d) 20 OMe H O 0.9  1.2 380 160.84≧134032 21 H OMe O 0.52 0.9 318070 142.41 >158228 22 OMe OMe O 0.04 0.8160 20.00 ≧25000 23 Cl H O — 1.8 700 86.34 47964 24 Cl OMe O — 0.6 15015.42 ≧25701 NVP 0.37 75.1 — 5.41 >72 DLV 72 — 0.86 12 EFV 3 5604.30 >1434 ^(a)IC₅₀: the concentration of an inhibitor that is requiredfor 50% inhibition of HIV-1 RT; ^(b)EC₅₀: half effect concentration,drug concentration that is required for half of individuals to produce aspecific effect; ^(c)CC₅₀: drug concentration required to reduce cellviability by 50%, i.e. drug concentration that is required for 50% celldeath; ^(d)SI: Selectivity index, the ratio of CC₅₀/IC₅₀.

The results show that, the compounds included by the general chemicalformula are non-nucleoside reverse transcriptase inhibitors, and possessstrong anti-HIV-1 virus activity, and slight cell toxicity and highselectivity index; and most of the compounds showed good inhibitionability against drug-resistant viral strain of L103N+Y181C.

Effect Example 3 Anti-HIV Biological Activity Test

HEPT and DDI were used as control substances, the inhibitory activitiesof a part of the target compounds are shown in Table 3.

TABLE 3 Anti-HIV activities and cell toxicities of compounds 25-54 onMT-4 cells EC50 (nM)^(a) Compounds R¹⁰ R⁸ Y HIV-1(IIIB) CC₅₀ (μM)^(b)SI^(c) 25 H 2-Me—Ph O 93.7 107.6 1148 26 H 4-Br—Ph O 263 235.1 894 27 H-3-Me—Ph O 625 >351.9 >563 28 H 4-MeO—Ph O 187 >3397.4 >1810 29 H2-MeO—Ph O 30 >185.6 >6186 30 H Ph O 887 >364.6 >411 31 H 4-Me—Ph O 42339.8 8091 32 H 2,4-diBr-6-Me—Ph O 17.6 156.9 8917 33 H -4-CN-2-Me—Ph O28 >333.0 >11893 34 H 2,4,6-triBr—Ph O 23 71 3087 35 H 2,6-diBr-4-Me—PhO 15 23.4 1563 36 H 2,4,6-triMe—Ph O 23 >34.1 >1484 37 H 2,4-diCl—Ph O28 113.9 4068 38 H 4-F—Ph O 156 310.0 1987 39 H 2-Cl—Ph O 57 343 6018 40H 4-Cl—Ph O 167 >395.6 >2369 41 H 4-CN-2,6-diMeO—Ph O 2.2 >93.1 >4231142 H 2,4,6-triCl—Ph O 3.5 244.4 69833 43 H 2,6-diMe—Ph O46 >639.5 >13902 44 H Ph S 752 494.1 657 45 H 4-CN-2,6-diMe—Ph O3.6 >172.2 >47832 46 H 4-CN-2,6-diEtO—Ph O 2.9 >99.3 >34239 47 H4-CN-2-EtO-6-^(n)PrO—Ph O 3.2 >66.7 >20842 48 H 2-Cl-4-CN-6-MeO—Ph O5.6 >173.0 >30899 49 H 2-Cl-4-CN-6-EtO—Ph O 5.9 >594.1 >10692 50 H4-CN-2-MeO-6-^(i)PrO—Ph O 6.7 >65.8 >9823 51 H Ph SO₂ 589 >215.0 >365 52H 4-CN-2-EtO-6-MeO—Ph O 2.6 >130.3 >50129 53 H 4-CN-2-MeO-6- O5.4 >57.7 >10691 54 Cl 2,4,6-Me—Ph O 1.8 147.0 81672BOE/BIRG587(nevirapine) 75.1 >15.02 >252 DDN/AZT 5.17 >93.548 >18094DMP266(efavirenz) 3 >6.336 >2174 ^(a)IC₅₀: the concentration of aninhibitor that is required for 50% inhibition of HIV-1 RT; ^(b)CC₅₀:drug concentration required to reduce cell viability by 50%, i.e. drugconcentration that is required for 50% cell death; ^(c)SI: Selectivityindex, the ratio of CC₅₀/IC₅₀.

The results show that, the compounds included by the general chemicalformula generally possess strong anti-HIV-1 virus activity, and slightcell toxicity and high selectivity index.

All the documents cited herein are incorporated into the invention asreference, as if each of them is individually incorporated. Further, itwould be appreciated that, in the above teaching of invention, theskilled in the art could make certain changes or modifications to theinvention, and these equivalents would still be within the scope of theinvention defined by the appended claims of the application.

What is claimed is:
 1. A compound or pharmaceutically acceptable saltsthereof, wherein the compound has the structure shown as the formula I:

wherein -a¹=a²-a³=a⁴- represents the structure of a divalent freeradical and is selected from: —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—,—N═N—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—; -b¹=b²-b³=b⁴- represents thestructure of a divalent free radical and is selected from:—CH═CH—CH═CH—, —N═CH—CH═CH—, —N═N—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—; R¹and R² respectively are separately selected from hydrogen, hydroxyl,halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆ alkenyl, substitutedC₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl, amino-group, —NH(OH)—,—N(R⁶)p—; R¹³ and R¹⁴ respectively are separately selected fromhydrogen, hydroxyl, halogen, substituted C₁₋₄ alkyl, substituted C₂₋₆alkenyl, substituted C₂₋₆ alkynyl, C₁₋₆ alkoxyl, cyano-group, nitryl,amino-group, —NH(OH)—, —N(R⁶)p—; R³ and R⁴ respectively are separatelyselected from hydrogen, hydroxyl, halogen, C₁₋₆ alkyl substituted bycyano-group or —C(═O)R⁶, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl substituted byone or more halogen atoms or cyano-groups, C₂₋₆ alkynyl substituted byone or more halogen atoms or cyano-groups, C₁₋₆ alkoxycarbonyl,carboxyl, cyano-group, nitryl, amino-group, —NR⁵—, methyl polyhalide,methoxyl polyhalide, methylthio polyhalide, —S(═O)_(p)R⁷,—NH—S(═O)_(p)R⁷, —C(═O)R⁷, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁷, and—C(═NH)R⁷; R⁵ represents hydrogen, C₁₋₆ alkycarbonyl, aryl, formoxyl,C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl; X is selected from —NR⁶—, —NH—NH—,—N═N—, —O—, —C(═O)—, C₁₋₄ alkanediyl, —CHOH—, —S—, —S(═O)p—, -X₁-C₁₋₄alkanediyl- or -C₁₋₄ alkanediyl-X₁-, and —CH(CN)—; X₁ is selected from—NR⁶—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, and —S(═O)p—; R⁶ isseparately selected from hydrogen, aryl, formoxyl, C₁₋₆ alkycarbonyl,C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted by formoxyl,C₁₋₆ alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl, C₁₋₆alkoxyl and C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl; R⁷is selected from amino-group-, —NH—NH—, mono- or di-(C₁₋₄ alkyl)amino-group and C₁₋₄ alkyl polyhalide, wherein where R³ is —S(═O)_(p)R⁷,R⁷ is selected from —NH—NH— and C_(1,4) alkyl polyhalide; m is aninteger from 0 to 5, n is an integer from 0 to 6; and P is an integer of1 or
 2. 2. The compound or pharmaceutically acceptable salts thereof ofclaim 1, wherein the compound has the structure shown as the formula II:


3. The compound or pharmaceutically acceptable salts thereof of claim 1,wherein the compound has the structure shown as the formula III:


4. The compound or pharmaceutically acceptable salts thereof of claim 1,wherein the salts are selected from hydrochloride, sulfate, tartrate,citrate, fumarate, and malate.
 5. A compound or pharmaceuticallyacceptable salts thereof, wherein the compound has the structure shownas the formula IV

wherein R⁸ is separately selected from aryl, substituted aryl, naphthyl,substituted naphthyl, 5- or 6-membered aromatic heterocyclic, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, and substituted aryloxycarbonyl; R⁹ andR¹⁰ respectively are separately selected from hydrogen, hydroxyl,halogen, C₁₋₆ alkoxyl, C₁₋₆ alkoxycarbonyl, carboxyl, cyano-group,nitryl, amino-group, —NR¹¹—, methyl polyhalide, methoxyl polyhalide,methylthio polyhalide, —S(═O)_(p)R¹², —NH—S(═O)_(p)R¹², —C(═O)R¹²,—NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹², and —C(═NH)R¹²; Z and Yrespectively are separately selected from —NR¹¹—, —NH—, —NH—NH—, —N═N—,—O—, —C(═O)—, C₁₋₄ alkanediyl, —CH(OH)—, —S—, —S(═O)p—, -X₂-C₁₋₄alkanediyl, -C₁₋₄ alkanediyl-X₂-, and —CH(CN)—; X² is selected from—NR¹¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CH(OH)—, and —S(═O)p—; R¹¹ isseparately selected from aryl, formoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted by formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl, C₁₋₆ alkoxyl andC₁₋₆ alkoxycarboxyl substituted by C₁₋₆ alkoxycarbonyl; R¹² is selectedfrom C₁₋₄ alkyl, amino-group, mono- or di-(C₁₋₄ alkyl) amino-group andC₁₋₄ alkyl polyhalide; m is an integer from 0 to 5, n is an integer from0 to 6; and P is an integer of 1 or
 2. 6. The compound of claim 5,wherein the pharmaceutically acceptable salts are selected fromhydrochloride, sulfate, tartrate, citrate, fumarate, and malate.
 7. Thecompound of claim 1, wherein X is —O—.
 8. The compound of claim 5,wherein Z is —O—.
 9. The compound of claim 1, wherein R3 is thecyano-group.
 10. A pharmaceutical composition, wherein thepharmaceutical composition comprises an effective dosage of a compoundor pharmaceutically acceptable salts thereof of claim 1, andpharmaceutically acceptable carriers.
 11. A pharmaceutical composition,wherein the pharmaceutical composition comprises an effective dosage ofa compound or pharmaceutically acceptable salts thereof of claim 5, andpharmaceutically acceptable carriers.
 12. A method of manufacturing amedicament, comprising mixing a compound or pharmaceutically acceptablesalts thereof in accordance with claim 1 with a pharmaceuticallyacceptable carrier.
 13. A method of manufacturing a medicament,comprising mixing a compound or pharmaceutically acceptable saltsthereof in accordance with claim 5 with a pharmaceutically acceptablecarrier.
 14. A method for preparing the compound in accordance withclaim 5, comprising: (a) mixing 4-chloro benzo pyrimidine, substitutedphenol or aniline, and polar aprotic solvent to react according to thefollowing general equation to obtain the compound in accordance withclaim 5;

or, comprising: (b) heating 2-chloro benzo pyrimidine and substitutedphenol or aniline to 150° C.-210° C. to fuse to react according to thefollowing general equation, to obtain the compound according to claim 5;

wherein, R⁸ is separately selected from aryl, substituted aryl,naphthyl, substituted naphthyl, 5- or 6-membered aromatic heterocyclic,C₁₋₆ alkoxycarbonyl, aryloxycarbonyl, and substituted aryloxycarbonyl;R⁹ and R¹⁰ respectively are separately selected from hydrogen, hydroxyl,halogen, C₁₋₆ alkoxyl, C₁₋₆ alkoxycarbonyl, carboxyl, cyano-group,nitryl, amino-group, —NR¹¹—, methyl polyhalide, methoxyl polyhalide,methylthio polyhalide, —S(═O)_(p)R¹², —NH—S(═O)_(p)R¹², —C(═O)R¹²,—NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹², and —C(═NH)R¹²; Z and Yrespectively are separately selected from —NR¹¹—, —NH—, —NH—NH—, —N═N—,—O—, —C(═O)—, C₁₋₄ alkanediyl, —CH(OH)—, —S—, —S(═O)p—, -X₂-C₁₋₄alkanediyl, -C₁₋₄ alkanediyl-X₂-, and —CH(CN)—; X₂ is selected from—NR¹¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CH(OH)—, and —S(═O)p—; R¹¹ isseparately selected from aryl, formoxyl, C₁₋₆ alkycarbonyl, C₁₋₆ alkyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl substituted by formoxyl, C₁₋₆alkycarbonyl, C₁₋₆ alkoxycarbonyl or C₁₋₆ alkycarboxyl, C₁₋₆ alkoxyl andC₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkoxycarbonyl; R¹² is selectedfrom C₁₋₄ alkyl, amino-group, mono- or di-(C₁₋₄ alkyl) amino-group andC₁₋₄ alkyl polyhalide. m is an integer from 0 to 5, n is an integer from0 to 6; and P is an integer of 1 or
 2. 15. The method of claim 14,wherein the reaction of step (a) is under the protection of inert gas,wherein the inert gas is argon, nitrogen, helium, or combinationsthereof.
 16. The method of claim 14, wherein the aprotic solvent used instep (a) is acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,tetrahydrofuran, or combinations thereof.
 17. The method of claim 14,wherein bases used in step (a) are selected from potassium carbonate,sodium carbonate, cesium carbonate, sodium hydride, sodium hydroxide,and potassium hydroxide.